Prodrugs for the Treatment of Schizophrenia and Bipolar Disease

Abstract

Compounds of Formula I and Formula II and their use for the treatment of neurological and psychiatric disorders including schizophrenia and manic or mixed episodes associated with bipolar I disorder with or without psychotic features is disclosed.

Description

RELATED APPLICATION(S)[0001]This application claims the benefit of U.S. Provisional Application Nos. 61 / 293,163 and 61 / 293,153, both filed on Jan. 7, 2010. The entire teachings of the above application(s) are incorporated herein by reference.BACKGROUND OF THE INVENTION[0002]Paliperidone, risperidone, iloperidone, lurasidone and ziprasidone are atypical antipsychotic drugs, all of which are approved by the U.S. Food and Drug Administration for the treatment of schizophrenia and bipolar mania. Two additional atypical antipsychotic drugs, perphenazine GABA ester (BL-1020) and perospirone have shown potential for treatment of schizophrenia and bipolar mania. The chemical structures of these heterocyclic compounds are given below.[0003]Other examples of heterocyclic derivatives that are useful for the treatment of schizophrenia and bipolar disorders are discussed in U.S. Pat. No. 5,350,747, U.S. Pat. No. 5,006,528, U.S. Pat. No. 7,160,888, and in U.S. Pat. No. 6,127,357. Heterocyclic der...

AI Technical Summary

Benefits of technology

[0017]The prodrug compounds of the invention incorporate a labile prodrug moiety which is cleaved in vivo to produce a bioactive compound such as paliperidone, risperidone, iloperidone, perospirone, lurasidone, or ziprasidone. Paliperidone, risperidone, iloperidone, lurasidone, perospirone, and ziprasidone are parent drugs from which prodrugs of the invention are derived that are useful in the treatment of schizophrenia and bipolar disorder. The addition of the prodrug moiety allows modification of the physical properties of these the parent drugs providing extended-release formulations. While a specific isomeric form of a parent drug may be preferred for use in treatment, the term “parent drug” as used herein is intended to encompass all isomers of the parent drug. It is also understood that the parent drug may be further “substituted” as that term is defined herein, for any purpose including but not limited to, stabilization of the parent during synthesis of the prodrug and stabilization of the prodrug for administration to the patient. One example of a substituted parent drug is a pharmaceutically acceptable ester of the parent drug. Any of the parent drugs and prodrugs of parent drugs of the invention may be substituted so long as the substituted parent drug or parent prodrug when administered to a patient in vivo becomes cleaved by chemical and / or enzymatic hydrolysis thereby releasing the parent drug moiety such that a sufficient amount of the compound intended to be delivered to the patient is available for its intended therapeutic use in a sustained release manner.

Problems solved by technology

While microencapsulation and enteric coating technologies impart enhanced stability and time-release properties to active agent substances, these technologies suffer from several shortcomings.

Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility.

Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent remaining available for sustained release.

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